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...ggested that bystander T cell activation might also serve as a disease trigger [40]. Bystander activation occurs when an infection causes T cells to acquire effector functions in a nonspecific manner =-=[41]-=-. Infection of BDC2.5 T cell receptor transgenic mice with coxsackie virus CB4 strain (a pancreatrophic virus) results in a 90% incidence of T1D [40]. Because BDC2.5+ CD4+ T cells recognize an islet a...

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...essing only the LCMV GP1 epitope (aa 33–41), (VV GP1), or VV expressing only the LCMV NP (VV NP). Construction of recombinant VV with LCMV GP, LCMV GP1 or LCMV NP followed by report of Mackett et al. =-=[51]-=-, and was confirmed by Northern blot analysis of LCMVspecific RNA [50]. For each, study, groups of four to five mice were infected, and their CTL profiles were investigated on three independent sample...

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... the RIP LCMV-NP tg model [20] as one specific CD8 T cell per 1000 total T cells were required to cause T1D. However, the RIP LCMV-NP model is limited by having only one known CTL epitope, NP 118–127 =-=[12,24,25]-=-, a lack of T cell receptor (TCR) tg mice, other genetically modified mice and reagents that are available for H-2b mice. Thus, in this report we switched to using RIP LCMV glycoprotein (GP) tg H-2b m...

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... of their ability to express the inflammatory cytokines IFN-c and TNF-a or display IL-2 in their cytoplasm were performed using our established and published assay for the T cell epitopes of LCMV ARM =-=[47,52,53]-=-. Briefly, for intracellular cytokine analysis and flow cytometry, splenocytes were stimulated with 2 mg/ml of MHC class I-restricted GP 33–41, GP 276–286, or 5 ml of MHC class II-restricted GP 67–80 ...

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...rly demonstrate that an overlap between a viral and self-protein can give rise to T1D following infection, others have suggested that bystander T cell activation might also serve as a disease trigger =-=[40]-=-. Bystander activation occurs when an infection causes T cells to acquire effector functions in a nonspecific manner [41]. Infection of BDC2.5 T cell receptor transgenic mice with coxsackie virus CB4 ...

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...portant to note, however, that bystander T cell activation is a relatively inefficient process estimated to occur in only 1 in 200 virus-specific CD8+ T cells infected with a non-overlapping pathogen =-=[42]-=-. Thus, the high frequency of islet-specific T cells in the repertoire of BDC2.5 mice likely favors the induction of T1D following coxsackie virus infection [40]. Importantly, when non-transgenic diab...

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...he remaining GP virusspecific CD8 T cells (5%) generated in the spleen (Fig. 2), subdominant GP-specific CD8 T cell responses are sufficient to protect the immunized mice from an acute LCMV infection =-=[27,30]-=-. The immunodominant CD4 epitope GP 67–80 within LCMV GPV generated anti-LCMV CD4 T cells (Fig. 1B), those virus-specific CD4 T cells failed to help the few (5%) Table 1. CTL specificity of wt and LCM...

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...ells. In addition, wt LCMV, GPV1 and GPV contained the subdominant GP 92–101, GP 118–125 and immunodominant nucleoprotein (NP) 396–404 CD8 CTL epitopes and the immunodominant CD4 CTL epitope GP 67–80 =-=[24,26,47,48]-=-. LCMV wt, GPV1 and LCMV GPV displayed normal migration in vivo [27]. 51Chromium (Cr) CTL assay The 51Cr-release assay was done 7 days after inoculating C57Bl/6 (H-2b) mice or Balb/cdj (H-2d) mice i.p...

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... T cells caused damage indirectly by first identifying the virus-infected target followed by a release of cytokines and chemokines which call in myeloid cells that also participate in cellular injury =-=[39]-=-. Whether a similar event occurs or plays a role in virus-induced diabetes is unknown. While our data clearly demonstrate that an overlap between a viral and self-protein can give rise to T1D followin...

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... required to cause diabetes [23]. By contrast, ratio of 1/6000 or less failed to cause disease [23]. These results were confirmed studying the role of cytokines/chemokines in the RIP LCMV-NP tg model =-=[20]-=- as one specific CD8 T cell per 1000 total T cells were required to cause T1D. However, the RIP LCMV-NP model is limited by having only one known CTL epitope, NP 118–127 [12,24,25], a lack of T cell r...

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...minate. Usually, more than 50% of the cells infiltrating pancreatic islets are CD8 CTL, and these are found at their b cell targets in association with an abundant expression of MHC class I molecules =-=[15,17,22]-=-. However, still unknown is what subpopulation and how many CTL specifically recognize the antigen(s) targeted in b cells causing their damage and inducing T1D. A confounding factor is the numerous by...

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...ls required for an autoimmune disease to develop, and once initiated, a pathogenic disease process does not need to rely on bystander T cells [44,45], although they may contribute to tissue pathology =-=[46]-=-. With the low levels of virus-specific T cells in the islets it is unlikely that bystander T cells play a role in T1D in our model. Host genes, autoimmune responses, cytokines/chemokines and virus ha...

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... of diabetes. Citation: Oldstone MBA, Edelmann KH, McGavern DB, Cruite JT, Welch MJ (2012) Molecular Anatomy and Number of Antigen Specific CD8 T Cells Required to Cause Type 1 Diabetes. PLoS Pathog 8=-=(11)-=-: e1003044. doi:10.1371/journal.ppat.1003044 Editor: James E. Crowe, Vanderbilt University Medical Center, United States of America Received July 9, 2012; Accepted October 4, 2012; Published November ...

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...minate. Usually, more than 50% of the cells infiltrating pancreatic islets are CD8 CTL, and these are found at their b cell targets in association with an abundant expression of MHC class I molecules =-=[15,17,22]-=-. However, still unknown is what subpopulation and how many CTL specifically recognize the antigen(s) targeted in b cells causing their damage and inducing T1D. A confounding factor is the numerous by...

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...ains (Armstrong [ARM], E350, Pasteur, Traub) that did or did not cause T1D. Results indicated that one effector virus-specific CD8 T cell per 785–1000 total CD8 T cells was required to cause diabetes =-=[23]-=-. By contrast, ratio of 1/6000 or less failed to cause disease [23]. These results were confirmed studying the role of cytokines/chemokines in the RIP LCMV-NP tg model [20] as one specific CD8 T cell ...

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...minate. Usually, more than 50% of the cells infiltrating pancreatic islets are CD8 CTL, and these are found at their b cell targets in association with an abundant expression of MHC class I molecules =-=[15,17,22]-=-. However, still unknown is what subpopulation and how many CTL specifically recognize the antigen(s) targeted in b cells causing their damage and inducing T1D. A confounding factor is the numerous by...

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...ells. In addition, wt LCMV, GPV1 and GPV contained the subdominant GP 92–101, GP 118–125 and immunodominant nucleoprotein (NP) 396–404 CD8 CTL epitopes and the immunodominant CD4 CTL epitope GP 67–80 =-=[24,26,47,48]-=-. LCMV wt, GPV1 and LCMV GPV displayed normal migration in vivo [27]. 51Chromium (Cr) CTL assay The 51Cr-release assay was done 7 days after inoculating C57Bl/6 (H-2b) mice or Balb/cdj (H-2d) mice i.p...

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...ells. In addition, wt LCMV, GPV1 and GPV contained the subdominant GP 92–101, GP 118–125 and immunodominant nucleoprotein (NP) 396–404 CD8 CTL epitopes and the immunodominant CD4 CTL epitope GP 67–80 =-=[24,26,47,48]-=-. LCMV wt, GPV1 and LCMV GPV displayed normal migration in vivo [27]. 51Chromium (Cr) CTL assay The 51Cr-release assay was done 7 days after inoculating C57Bl/6 (H-2b) mice or Balb/cdj (H-2d) mice i.p...

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...uggest a lytic role for CD8 T cells in destroying b cells to cause T1D. In addition, inflammatory cytokines like interferon-c generated by virus-specific CD8 T cells are important contributors to T1D =-=[38]-=-. Interestingly, in LCMV-induced acute leptomeningitis, LCMV-specific CD8 T cells caused damage indirectly by first identifying the virus-infected target followed by a release of cytokines and chemoki...

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...% (58/4241 cells from 38 islets) were GP33specific at 10 days post-infection. Earlier studies determined that the fidelity of this in situ tissue tetramer technique compared favorably to that of FACS =-=[31]-=-. For those studies GP33 T cell receptor (TCR) tg mice were sacrificed, spleens removed and virus-specific CD8 T cell numbers quantified by flow cytometry versus in situ GP33 tetramer staining in the ...

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...T cells were able to diminish or abort diabetes [34– 36]. Additionally, the number of effector CD8 T cells, as documented in Listeria infection, appears tightly controlled by TGF-b-mediated apoptosis =-=[37]-=-. This suggests that TGF-b and likely other factors may also play a role in our in vivo analysis of the generation of effector CD8 T cells. Analysis of interactions at the immunologic synapse between ...

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... of b cell damage in T1D has been attributed to the host’s own immune response. Information based on biopsied or autopsied pancreases from humans [14–17] and study of relevant animal models (reviewed =-=[18]-=- has identified numerous effector cells such as CD8 cytotoxic T cells (CTL), CD4 T cells, macrophages, B cells and NK cells in the islets. Other players in this action are cytokine/ chemokines like IF...

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... known GP CD8 T cell epitopes: immunodominant GP 33– 41.GP 276–286 and subdominant GP 92–101 and GP 118–125. Utilizing LCMV ARM wt or viral variants of LCMV ARM in which CD8 CTL epitopes were mutated =-=[26,27]-=- along with GFPlabeled TCR GP33 CTLs and tetramers allowed us for the first time to identify the numbers of virus-specific CD8 T cells from the PLOS Pathogens | www.plospathogens.org 1 November 2012 |...

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...ncidence .94%). Previous studies indicated that CD4 T cells failed to play a role in this model, since their depletion did not alter either the kinetics or incidence of the resultant diabetic disease =-=[12,28]-=-. This result stands in contrast to a model in which the viral transgene was expressed both in the b cells and in the thymus. In this model, antiLCMV CD8 T cells of high affinity are selected out in t...

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...P67-specific CD4 T cells (Fig. 1B) [24,26,27]. We next determined the ability of wt LCMV ARM, GPV1 and GPV viruses to cause T1D in C57Bl/6 (B6) RIP-LCMV GP mice. As anticipated from our prior reports =-=[12,25,28,29]-=-, inoculation of RIP-LCMV GP tg mice with 16105 PFU of LCMV ARM i.p. induced T1D in all mice (Fig. 2, left panel). By four weeks postinfection with wt LCMV ARM, all mice had blood glucose levels of .3...

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...elected out in the thymus with antiviral CD8 T cells of lower affinity going to the periphery. To cause T1D, virus-induced specific CD4 T cells in addition to virus-specific CD8 T cells were required =-=[12,28,33]-=-. The full-length viral GP in H-2b mice has only four distinct CD8 CTL epitopes that recognize two immunodominant LCMV epitopes, GP33 and GP276, as well as two weaker subdominant CD8 CTL epitopes, GP9...

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...uction of T1D following coxsackie virus infection [40]. Importantly, when non-transgenic diabetes-prone NOD mice were infected with coxsackie virus, the pathogen could accelerate but not initiate T1D =-=[40,43]-=-. These data suggest that viruses may accelerate autoimmune diseases through bystander activation once a critical threshold of self-reactive T cells is reached. A shared epitope between a viral and se...

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...nt mechanism to generate the number of self-reactive T cells required for an autoimmune disease to develop, and once initiated, a pathogenic disease process does not need to rely on bystander T cells =-=[44,45]-=-, although they may contribute to tissue pathology [46]. With the low levels of virus-specific T cells in the islets it is unlikely that bystander T cells play a role in T1D in our model. Host genes, ...

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...nt mechanism to generate the number of self-reactive T cells required for an autoimmune disease to develop, and once initiated, a pathogenic disease process does not need to rely on bystander T cells =-=[44,45]-=-, although they may contribute to tissue pathology [46]. With the low levels of virus-specific T cells in the islets it is unlikely that bystander T cells play a role in T1D in our model. Host genes, ...

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...0:1 and 25:1 to H-2b (MC57) or H-2d (Balb Cl7) target cells. Target cells were pre-labeled with 51Cr and infected with LCMV ARM or various vaccinia virus (VV) constructs expressing LCMV GP components =-=[25,26,49,50]-=-. We used VV expressing whole LCMV GP (VV GP), VV expressing only the LCMV GP1 epitope (aa 33–41), (VV GP1), or VV expressing only the LCMV NP (VV NP). Construction of recombinant VV with LCMV GP, LCM...

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...1 as described in Materials and Methods. The generation, selection, sequencing and specificity of GPV1 and GPV have been published [26,27]. Target cells H-2b (MC-57) and H-2d (Balb Cl 7) as described =-=[25,26,50]-=- were infected with LCMV ARM or VV constructs expressing the whole wt LCMV nucleoprotein (NP), whole LCMV GP, or just the N-terminal component of GP containing the GP-33 CTL epitope but not the GP-276...

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... of their ability to express the inflammatory cytokines IFN-c and TNF-a or display IL-2 in their cytoplasm were performed using our established and published assay for the T cell epitopes of LCMV ARM =-=[47,52,53]-=-. Briefly, for intracellular cytokine analysis and flow cytometry, splenocytes were stimulated with 2 mg/ml of MHC class I-restricted GP 33–41, GP 276–286, or 5 ml of MHC class II-restricted GP 67–80 ...